4-(benzo[b]thiophen-2-yl)-2-hydroxy-4-oxobut-2-enoic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻吩类
• 英文名称: 4-(benzo[b]thiophen-2-yl)-2-hydroxy-4-oxobut-2-enoic acid
• 英文别名: 4-(1-benzothiophen-2-yl)-2-hydroxy-4-oxobut-2-enoic acid
• 化学式: C₁₂H₈O₄S
• 分子量: 248.259
• InChiKey: STFIWEHEAIGNHT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.61
• 重原子数：
  17.0
• 可旋转键数：
  3.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  74.6
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为产物：
  描述：

  2-乙酰基苯并噻吩 在 sodium ethanolate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 1.25h， 生成 4-(benzo[b]thiophen-2-yl)-2-hydroxy-4-oxobut-2-enoic acid
  参考文献：
  名称：

  Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition

  摘要：

  Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Here we report the synthesis and biological evaluation of a new series of alpha,gamma-diketo acids (DKAs) as NS5B polymerase inhibitors. We initiated structure-activity relationship (SAR) optimization around the furan moiety of compound 1a [IC50 = 21.8 mu M] to achieve more active NS5B inhibitors. This yielded compound 3a [IC50 = 8.2 mu M] bearing the 5-bromobenzofuran-2-yl moiety, the first promising lead compound of the series. Varying the furan moiety with thiophene, thiazole and indazole moieties resulted in compound 11a [IC50 = 7.5 mu M] bearing 3-methylthiophen-2-yl moiety. Finally replacement of the thiophene ring with a bioisosteric phenyl ring further improved the inhibitory activity as seen in compounds 21a [IC50 = 5.2 mu M] and 24a [IC50 = 2.4 mu M]. Binding mode of compound 24a using glide docking within the active site of NS5B polymerase will form the basis for future SAR optimization. (C) 2011 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2011.08.028

文献信息

• Inhibitors of Mycobacterium Tuberculosis Malate Synthase, Methods of Making and Uses Thereof
  申请人：Freundlich Joel S.

  公开号：US20140171444A1

  公开（公告）日：2014-06-19

  The present invention provides aryl- or heteroaryl-diketo acid compounds effective to inhibit an activity of a Mycobacterial malate synthase enzyme or to inhibit a malate synthase activity in other bacteria having the enzyme. The compounds may be phenyl- naphthyl-, or thienyl-substituted diketo acids and carboxylate derivatives thereof. Also provided are methods of treating tuberculosis or other pathophysiological conditions associated with a malate synthase enzyme with the inhibitory compounds and methods of in silico design of the inhibitory compounds. In addition, the present invention provides the inhibitory compounds designed by this method. Furthermore, three-dimensional X-ray crystal structures of the Mycobacterial malate synthase complexed with the inhibitory compounds are provided. Further still a method for stabilizing an aromatic or heteroaromatic diketo acid or its prodrug or close analog in solution by derivatizing at least the ortho position on the aromatic ring is provided.

  本发明提供了芳基或杂环芳基二酮酸化合物，其能够有效抑制结核分枝杆菌苹果酸合酶酶活性或抑制其他具有该酶的细菌的苹果酸合酶活性。这些化合物可以是苯基、萘基或噻吩基取代的二酮酸和其羧酸衍生物。还提供了使用这些抑制剂治疗结核病或其他与苹果酸合酶酶相关的病理生理状况的方法以及通过计算机模拟设计这些抑制剂的方法。此外，本发明还提供了通过这种方法设计的抑制剂。此外，还提供了与抑制剂形成复合物的结核分枝杆菌苹果酸合酶的三维X射线晶体结构。还提供了一种通过在芳香环上至少衍生化邻位位置来稳定溶液中的芳香或杂环芳香二酮酸或其前药或类似物的方法。
• Inhibitors of mycobacterium tuberculosis malate synthase, methods of making and uses thereof
  申请人：Freundlich Joel S.

  公开号：US20100113477A1

  公开（公告）日：2010-05-06

  The present invention provides aryl- or heteroaryl-diketo acid compounds effective to inhibit an activity of a Mycobacterial malate synthase enzyme or to inhibit a malate synthase activity in other bacteria having the enzyme. The compounds may be phenyl-naphthyl-, or thienyl-substituted diketo acids and carboxylate derivatives thereof. Also provided are methods of treating tuberculosis or other pathophysiological conditions associated with a malate synthase enzyme with the inhibitory compounds and methods of in silico design of the inhibitory compounds. In addition, the present invention provides the inhibitory compounds designed by this method. Furthermore, three-dimensional X-ray crystal structures of the Mycobacterial malate synthase complexed with the inhibitory compounds are provided. Further still a method for stabilizing an aromatic or heteroaromatic diketo acid or its prodrug or close analog in solution by derivatizing at least the ortho position on the aromatic ring is provided.
• US8664255B2
  申请人：——

  公开号：US8664255B2

  公开（公告）日：2014-03-04
• Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition
  作者：Aaditya Bhatt、K.R. Gurukumar、Amartya Basu、Maulik R. Patel、Neerja Kaushik-Basu、Tanaji T. Talele

  DOI：10.1016/j.ejmech.2011.08.028

  日期：2011.10

  Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Here we report the synthesis and biological evaluation of a new series of alpha,gamma-diketo acids (DKAs) as NS5B polymerase inhibitors. We initiated structure-activity relationship (SAR) optimization around the furan moiety of compound 1a [IC50 = 21.8 mu M] to achieve more active NS5B inhibitors. This yielded compound 3a [IC50 = 8.2 mu M] bearing the 5-bromobenzofuran-2-yl moiety, the first promising lead compound of the series. Varying the furan moiety with thiophene, thiazole and indazole moieties resulted in compound 11a [IC50 = 7.5 mu M] bearing 3-methylthiophen-2-yl moiety. Finally replacement of the thiophene ring with a bioisosteric phenyl ring further improved the inhibitory activity as seen in compounds 21a [IC50 = 5.2 mu M] and 24a [IC50 = 2.4 mu M]. Binding mode of compound 24a using glide docking within the active site of NS5B polymerase will form the basis for future SAR optimization. (C) 2011 Elsevier Masson SAS. All rights reserved.